1-chloro-2,2,2-trifluoroethyl difluoromethyl ether



3,535,388 1-CHLORO-2,2,2-TRIFLUOROETHYL DIFLUOROMETHYL ETHER Ross C.Terrell, Summit, N..I., assignor to Air Reduction Company, Incorporated,New York, N.Y., a corporation of New York No Drawing. Originalapplication Dec. 15, 1967, Ser. No. 690,771. Divided and thisapplication Mar. 21, 1969, Ser. No. 823,873

Int. Cl. C07c 43/00, 43/12 US. Cl. 260-614 1 Claim ABSTRACT OF THEDISCLOSURE This application discloses the novel compound l-chloro2,2,2-trifiuoroethyl difiuoromethyl ether having the formula CFCHClO-CHF The compound is prepared through stepwise chlorination andfluorination reactions starting with the trifluoroethyl methyl ether.The compound is useful as an anesthetic and as a solvent and dispersantfor fiuorinated materials.

CROSS REFERENCE TO RELATED APPLICATION This is a division of copendingapplication Ser. No. 690,771 filed Dec. 15, 1967 for Compositions.

DESCRIPTION OF THE INVENTION This invention relates to the compoundl-chloro-2,2,2- trifiuoroethyl difluoromethyl ether, its preparation andits use in producing anesthesia in anesthetic susceptible air breathingmammals.

The compound l-chloro-2,2,2-trifluoroethy1 difluoromethyl ether has thefollowing formula:

It is normally a clear, colorless liquid with a very slight odor. It hasthe following physical properties: boiling point 48.5 C.; vapor pressure330 mm. at 25 C.; specific gravity 1.45; refractive index N 1.3002 andmolecular weight 174.5. The compound is nonflammable, soda lime stable,and is a potent anesthetic for inhalation anesthetic susceptiblemammals. The compound is also easily miscible with other organic liquidsincluding fats and oils and has useful solvent properties, for example,as a solvent for fluorinated olefins and other fluorinated materialssuch as fiuoro waxes. It may be used to prepare pastes and dispersionsof such materials useful for coatings and the like and may be used as adegreasing agent.

There are at present two preferred procedures for the preparation of1-chloro-2,2,2-trifiuoroethyl difluoromethyl ether. The basic startingmaterial for both procedures is trifluoroethanol CF CHOH a readilyavailable commercial material.

The trifluoroethanol CF CH OH is first converted to the methyl etherprecursor by reacting it with dimethylsulfate (CH SO in either anaqueous or nonaqueous medium. An aqueous alkaline solution of potassium,sodium, or lithium hydroxides can be used as well as nonaqueous mediasuch as dioxane, benzene, liquid hydrocarbons, tetrahydrofuran ordiethyl ether. The preferred reaction medium is aqueous potassiumhydroxide.

The etherification reaction can be carried out at any temperature up tothe boiling point of the reaction mixture. The reaction is exothermic soit is preferred to use water cooling to control the rate of reaction.With a slight amount of water cooling and adequate stirring the reactioncan be easily maintained at room temperature, approximately 2030 C.

The reaction is very rapid with the dimethyl sulfate (CH SO reactingalmost as fast as it is added. The

reaction time is not critical, however, as in most organic reactions itis preferred to let the reaction proceed for 2 to 3 hours. The (CH SOshould be free of acid for best results. On completion of theetherification reaction the ether can be separated from the reactionmass by fractional distillation.

The halogenation of the methyl ether precursor to form CF CHClOCHF canbe carried out through either of two procedures. In the first procedureis chlorinated to form CF CHClOCHCl which is subsequently fiuorinated toform the desired CF CHClOCHF In the second procedure CF CH OCH ispartially chlo rinated to form CF CH OCHCI The partially chlorinatedproduct is then fiuorinated to produce CF CH OCHF The fluorinatedproduct is again chlorinated to form the desired product CF CHClOCHF Thechlorination of CF CH O--CH to form CF CHClOCHCl should be carried outin either a fully or partially transparent vessel so that photo energycan be supplied to the reaction. Suitable sources of photo energy areincandescent, ultraviolet and fluorescent lamps and even strong sunlight. In view of the ready availability, low cost and ease of handlingof incandescent lamps they are preferred for use as the illuminationsource.

The chlorination reaction is carried out by bubbling gaseous chlorineinto the liquid CF CH 0CH while it is strongly illuminated. The chlorineis added at the same rate at which it reacts which can be determined bychecking for chlorine vapor in the efiluent from the ch10- rinator. Thereaction is exothermic so cooling water should be supplied to thechlorination apparatus to control the reaction. The chlorination can becarried out at any temperature from 15 C. up to the boiling point of thechlorination mixture. Best results are usually found at 2535 C. wherethe reaction rate is fast enough and the formation of byproducts doesnot present a serious problem.

The effluent from the chlorination apparatus should be passed through awater scrubber to dissolve the HCl which is formed. The chlorinationshould be continued until 2.5-3 moles of HCl per mole of starting etherare detected by titration of the dissolved HCl with a standard base. Theextent of the chlorination can be controlled by the amount of chlorinebubbled through the ether and determined by the amount of efiluent HCl.If too little HCl is evolved it indicates that the chlorination productsare predominantly the mono or dichloro product. If too much HCl isdetermined it indicates that polychloro products have been formed orthat the ether has decomposed into undesirable chlorinated reactionproducts.

Following the chlorination the reaction mass can be separated byfractional distillation or by vapor phase chromatography. Ifdistillation is employed it is recommended that the pressure be reducedin view of the high molecular weight of the product CF CHClOCHClExcessive heating should obviously be avoided in view of the possibilityof decomposition of the desired product.

The thus preparation CF CHClOCHCl should then be transferred to areaction vessel that will not be attacked during the fluorinationreaction. A stainless steel, copper, nickel, or platinum vessel would bequite suitable. A catalyst such as SbCl SnCL, or SbF should be added tothe chlorinated starting material before beginning the fluorination. Thefluorination reaction can be carried out by bubbling gaseous HF throughthe reaction mixture or by adding solid SbF to the mixture.

The fiuorination reaction is preferably carried out at C. Higher orlower temperatures can be employed, however, it has been found thathigher temperatures produce undesirable reaction products while lowertemperatures cause a slow rate of reaction.

The effluent from the fiuorination apparatus should be passed through awater scrubber to collect the HCl which is formed during the reaction.The amount of HCl formed is equivalent to the number of chlorine atomsexchanged for fluorine. Too much HCl evolved indicates either overfiuorination or decomposition. The fiuorination should be continueduntil approximately two moles of HCl are collected for each mole of CFCHClOCHCl indicating that two chlorine atoms have been exchanged. Thepreferred site for the fiuorination is on the chlorine substitutedmethyl group resulting in the formation of The desired reaction productcan be readily separated from the reaction mixture by fractionaldistillation.

In the alternative method of preparation, methyl ether precursor CF CHO-CH is chlorinated in an apparatus similar to that previouslydescribed, however, only 1.8-2 moles of chlorine are added to form As inthe previous chlorination reaction the extent of chlorination ismonitored by determining the amount of effiuent HCl. The reactionproduct can be separated by fractional distillation at reduced pressureor by vapor phase chromatography.

The dichlorinated product is then fluorinated as in the final step ofthe first process to form OF CH OCHF The fiuorination reaction can becarried out in a similar apparatus and under essentially the sameconditions. In this fiuorination reaction it is not necessary to employa catalyst, however, a catalyst can be used to speed up the rate ofreaction.

Following the fiuorination the CF CH -O-CHF is separated from thereaction mixture by fractional distillation. The product is thenreturned to the chlorination apparatus used previously and achlorination reaction is carried out under essentially the sameconditions. The reaction is continued until one mole of HCl is collectedper mole of CF CH O'-C-HF indicating that one chlorine atom has beenadded. The preferred site for addition of the chlorine is on themethylene group adjacent to the ether oxygen. The resulting CF CHC1OOHIFcan be separated from the reaction mixture by fractional distillation.

'Either one of the two procedures disclosed can be used for thepreparation of CF CHClO-CHF The second procedure has a slight advantagein that fewer highly chlorinated reaction products are formed in thepartial chlorination, and any monochlorinated product formed can berecycled to the chlorinator for further chlorination and subsequent use.

The following examples will illustrate the procedural steps leading tothe preparation of 1-chlor0-2,2,2-tr ifluoroethyl difluoromethyl ether.

EXAMPLE 1 Preparation of the intermediate CF CH OCH To a solution of 86grams of KOH in 100 ml. of Water there was added dropwise with stirring100 grams (1 mole) of CF CH OH. To this solution there was then addeddropwise and with stirring 164 grams (1.3 moles) of (CH SO The reactionmixture was allowed to stir for several hours while being maintained at30 C. with water cooling. The resulting ether was then distilled using aDean Stark trap and 113 grams were collected. The resulting ether wasanalyzed by means of vapor phase chromatography and found to be 99.32%pure.

4 EXAMPLE 2 Preparation of CF CHClOCHCl Approximately 456 grams (4moles) of CF CH OCH prepared as illustrated in Example 1, Were added. toa Water jacketed chlorinator fitted with a thermometer, a Dry-Ice coldfinger type condenser and a fritted glass gas dispersion tube. Thereaction was carried out at 25 C. with gaseous chlorine being bubbledthrough the solution which was exposed to a source of illumination. Theefiluent HCl was collected in a scrubber and aliquots were titrated witha standard base. The reaction was continued until 2.8 moles of HCl permole of ether were titrated. Following the chlorination 805 grams of amaterial having a refractive index N 1.3860 were recovered. Theincreased weight of the reactants corresponds to 2.5 moles of chlorineadded per mole of starting ether.

The resulting material was flash distilled through a 60 X 1.5 cm.Vigreux column to yield 797 grams of a material with a boiling range of5372 C. at 150 mm. of mercury and having the following composition asdetermined by vapor phase chromatography:

Percent CF CH OCHCl 18 CF CH OCCl 30 CF CHClO CHCl 34 CF CHClOCCl 18This mixture was separated by fractional distillation to yield:

122 g. of CF CH OCHCl B.P. 47-48 at 150 mm. N

1.3670 (99% pure).

196 g. of CF CH OCCl B.P. 58-59 at 150 mm. N

1.3865 pure).

180 g. of CFgCHClOOHClZ, B.P. 59-64 at 150 mm.

N 1.3885 pure).

g. of CFgCHClOCClg, B.P. 64-65 at mm. N

1.4040 (97% pure).

Pure samples of each of these compounds were prepared by preparative gaschromatography and the structures were determined by elemental analysisand N.M.R. and infrared spectral analyses.

EXAMPLE 3 Preparation of CF CHClOCI-IF A l-liter 3-necked stainlesssteel flask was fitted with a copper Dry-Ice cold finger condenser, astainless steel stirring shaft and gland and a copper gas inlet tube. Tothe flask there was then added 50 grams (0.23 mole) of CF CHClOCHCl asprepared in Example 2 and 1.5 grams of SbCl HF gas was then slowlybubbled through the stirred mixture which was maintained at 0 C. Thereaction was run until 0.35 mole of HCl was collected, as indicated bythe tiration of the eflluent gas which was dissolved in water. Followingthe fiuorination 26 grams of material were recovered and determined tobe 90% pure by vapor phase chromatography. Fractional distillation usinga 30 x 0.5 cm. column packed with glass helices gave the pure product,B.P. 48-48.5 C., N 1.3002. The structure CF CHClOCHF was determined byelemental analysis, N.M.R. and infrared spectra.

EXAMPLE 4 Preparation of CF CH OCHCl In an alternative method ofpreparation, 305.5 grams (2.72 moles) of CF CH OCH prepared asillustrated in Example 1 were added to a water jacketed chlorinatorfitted with a thermometer, a Dry-Ice cold finger type condenser and afritted glass gas dispersion tube. The reaction was carried out at 25 C.with gaseous chlorine being bubbled through the solution which wasexposed to a source of illumination. The efiluent HCl was collected inan aqueous scrubber and aliquots were titrated with standard base. Thereaction was continued until slightly less than 2.0 moles of HCl permole of ether were titrated. The reaction product was then distilled asin Example 2 to yield 361 grams of CF CH OCHCl iden tical to theproduct, B.P. 4748 at 150 mm. N 1.3670 described in Example 2.

EXAMPLE 5 Preparation of CF CH OCHF In an apparatus similar to thatemployed in Example 3 420 grams of CF CH OCHCI were fluorinated using1.5 g. of SbCl as a catalyst. Following the fiuorination 335 grams ofmaterial were recovered and distilled through a 60 x 2 cm. column packedwith glass helices to yield 182 grams of a material with a boiling pointof 29 C. and a refractive index of N 1.2653. Upon examination by vaporphase chromatography the material was found to be 99% pure. Elementalanalysis showed the compound to have the empirical formula C H F O andstructural analysis using LR. and N.M.R. identified the compound asCFgCHgOCHFz.

EXAMPLE 6 Preparation of CF CHC1OCHF Into a small chlorination apparatusequipped with a Dry-Ice trap there was placed 129 grams of CF CH OCHHThe apparatus was purged with nitrogen for 2 minutes. Gaseous chlorinewas then bubbled through the liquid while it was illuminated with anincandescent light. The efliuent HCl was titrated until approximatelyone mole of HCl was collected. The reaction product weighed 140 gramsindicating an increase in weight of 11 grams. The product was thendistilled through a 60 x 2 cm. stainless steel packed column to givepure CF CHClOCHF identical to material prepared in Example 3.

In order to determine the potency of 1-chloro-2,2,2- trifluorethyldifluoromethyl ether as an inhalation anesthetic in combination withoxygen a series of tests were carried out on both mice and dogs. The1-chloro-2,2,2- trifluoroethyl difluoromethyl ether used was at least99.5% pure as determined by vapor phase chromatography.

Groups of five mice were placed into a jar and exposed to aconcentration of 1.25% by volume of l-chloro- 2,2,2-trifluorethyldifluoromethyl ether. After an induction time of 1.65 minutes, which wasfree of excitation, the mice were anesthetized. During the period ofanesthesis the mice showed no change in respiration and no visibleuntoward effects. The mice recovered in 1.1 minutes following removalfrom the jar and showed no after effects.

Groups of 5 more mice were than given a similar test with 2.5% by volumeof the compound. After an induction time of 0.5 minutes an excellentanesthetic syndrome was produced. Anesthesia was deep and relaxationexcellent. The induction period was very smooth with no apparentexcitation. On removal from the jar the mice fully recovered in 2.35minutes with no delayed deaths.

Four mongrel dogs weighing between 9.2 and 13.6 kgs. were anesthetizedusing a closed circuit infant inhalation set. An inhaled concentrationof 2.5 to 3% of l-chloro- 2,2,2-trifiuorethyl difluoromethyl in pureoxygen was administered throughout the anesthesis. No premedication wasused. The compound produced a smooth induction and uneventful recoveryin the dogs. No excitation was noted during induction or recovery. Theagent handled easily, most likely because of its low boiling point of48.5 C. The desired anesthetic level was easily maintained, relaxationwas excellent and analgesia was present until recovery. Some salavationwas noted in two dogs during recovery, however, the agent did not appearto be irritating to the mucous membranes. No tremor or twitching werenoted in any of the dogs.

While the dogs were in a surgical plane of anesthesia 10 gamma/kg. ofepinephrine was administered intravenously. The electrocardiogram showedcomplete two to one and three to one heart block which did not last morethan four minutes. The beats that came through were normal. In one dogthere was partial inversion of the QRS complex which rapidly returned tonormal. All dogs recovered rapidly and uneventfully from the epine hrinechallenge. There were no signs of auricular or ventricular tachycardiaor fibrillation in any of the dogs.

The compound l-chloro-Z,2,2-trifiu0roethyl difluoromethyl ether exhibitsexcellent anesthetic properties in inhalation anesthetic susceptiblemammals. The compound is non-flammable and soda lime stable. It lendsitselfs to effective use as an inhalant anesthetic in respirablemixtures containing life-supporting concentrations of oxygen. Inaddition, studies with the agent have shown that it is highly potent,affords good muscular relaxation, is nontoxic, has a high margin ofsafety, aflfords rapid induction free of excitation and rapid recovery,affords ease of control of the level of anesthesia and is compatiblewith ancillary drugs commonly used in connection with anesthesia.

The eifective amount of CF CHClO-CHF to be employed depends on the levelof anesthesia to which the mammal is to be brought, the rate at whichanesthesia is to be induced, and the length of time over whichanesthesia is to be maintained. Volume percentages of CF CHClO-CHF inoxygen from a fraction of a percent up to several percent, can beemployed. The person controlling the anesthesia can easily regulate theamount of CF CHCIO'CHF to be used starting with a small amount of theether and gradually increasing the amount until the desired plane ofanesthesia is reached. By then monitoring the physical properties of themammal, as is the usual procedure, the duration and plane of anesthesiacan be readily controlled.

It should be understood that the foregoing disclosure relates only to apreferred embodiment of the invention and that it is intended to coverall changes and modifications of the example of the invention hereinchosen for the purpose of the disclosure which does not constitutedeparture from the spirit and scope of the invention.

I claim:

1. The compound 1-chloro-2,2,2-trifluoroethyl difluoromethyl ether ofthe formula CF CHClOCHF References Cited UNITED STATES PATENTS 2,066,9051/1937 Booth. 2,803,665 8/1957 Miller et al. 2,803,666 8/1957 Miller eta1. 3,278,615 10/1966 Larsen et a1.

OTHER REFERENCES Henne et al.: J. Am. Chem. Soc., 74 (1952), pp. 5420-5422.

Park et al.: J. Am. Chem. Soc., 74 (1952), pp. 2292- 2294.

Park et al.: I. Am. Chem. 50., 76 (1954), pp. 1387- 1388.

Mitsch et al.: I. Heterocyclic Chem., 2 (1965), pp. 152-156.

Clayton et al.: J. Chem. Soc. (1965), p. 7377. Hudlicky: Chemistry ofOrganic Fluorine Compounds, MacMillan Co., New York (1962) pp. 9l97.

HOWARD T. MARS, Primary Examiner U.S. Cl. X.R.

UNITED STATES PATENT OFFICE CERTIFICATE OF CORRECTION Patent No. 3, 535,388 Dated OC o'dbel T711, 197*] oss C.

Inventor(s) It is certified that error appears in the above-identifiedpatent and that said Letters Patent are hereby corrected as shown below:

j n I Go] l, in the headl mg, ohe gerlal No. reaos "893,0 3'

and should read --9'52, fi'3 Col. 1, line 5, "cF cHoH" should read CF CHOH-. Col. 2, line 63, "preparation" should read prepa1"ed. Col. 3, line12, after "fluorine. add the following:

Too little HCl evolved indicates incomplete exchange.-

line 1?, after HCl evolved" should he omitted.

Col. 5, 11 he 72, OCHH should read OCHF line 6 "anesthesis" should read"anesthesia".

001.6, line 15, "selfis" should read --self.

Signed and sealed this 22nd day of June 1 971 (SEAL) Attest:

p n mpn M FT-ETQHRR' TR WILLIAM E. SCHUYLER, JR-

lines Pi- L9, "anesthesis should read --anesthesia Attesting OfficerCommissioner of Patents FORM F G- 050 uscoMM-Dc 6U376-F'69 Q U SGOVEQNHENY PRINTING OFFCE IQ! 0-365!Jl

